Study Questions:

What is the effect of angiotensin-receptor-neprilysin inhibition on mode of death in heart failure (HF)?

Methods:

The study cohort was comprised of 8,399 New York Heart Association class II-IV chronic systolic HF patients enrolled in the PARADIGM-HF (Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized double-blind trial comparing enalapril with angiotensin-receptor-neprilysin inhibitor LCZ696. Median follow-up period was 27 months, and mode of death was adjudicated by blinded clinical endpoints committee.

Results:

The study investigators found that 1,546 patients, including 711 (17.0% of total patients) in the LCZ696 group and 835 patients (19.8%) in the enalapril group, died during the trial (hazard ratio [HR] for death from any cause, 0.84; 95% confidence interval [CI], 0.76-0.93). Of the deaths, 1,251 (80.9% of deaths) were ascribed to cardiovascular causes, including 558 deaths (13.3% of total patients) in the LCZ696 group and 693 (16.5%) in the enalapril group. Therefore, LCZ therapy, when compared to enalapril, reduced the risk of overall cardiovascular mortality (HR, 0.80; 95% CI, 0.72-0.89; p < 0.001). This reduction in risk of death by LCZ therapy was by reducing both sudden death (HR, 0.80; 95% CI, 0.68-0.94; p = 0.008) and death due to worsening HF (HR, 0.79; 95% CI, 0.64-0.98; p = 0.034).

Conclusions:

The authors concluded that angiotensin-receptor-neprilysin inhibition with LCZ696, when compared with enalapril, was superior in reducing sudden cardiac death and mortality from worsening HF.

Perspective:

The substantial reduction of cardiovascular mortality with angiotensin-receptor-neprilysin inhibition raises important questions about the precise mechanism by which it does so. Understanding the mechanism of benefit of LCZ696 should provide a better understanding of the pathophysiology of HF.